Predictive indicators for revisional surgery in nasal reconstruction after Mohs surgery

Background: Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders of anatomical subunits. Reconstructive challenges can lead to multiple revisional surgeries to achieve the final aesthetic result. This study aimed to evaluate risk factors and predictors of revisional surgery in patients undergoing reconstruction after Mohs micrographic surgery for nasal tumours. Methods: This was a prospective cohort study from April 2, 2008 to February 26, 2019. The study population included all consecutive patients who underwent Mohs micrographic surgery for nasal skin cancer. Resection and reconstruction of nasal skin cancer was performed by the Mohs team. Results: A total of 988 cases met our study inclusion criteria with 64 (6.5%) cases requiring unplanned surgical revision. Revision rates were highest in the ala (9.0%, p < 0.05) and complex anatomical subunits (16.7%, p < 0.0001). In contrast, revision rates for dorsum lesions were lowest (1.8%, p < 0.001). In terms of reconstructive modalities, local flaps resulted in significantly higher rates of revision when compared to grafts (relative risk, 2.37; 95% CI, 1.15–5.0; p < 0.01). In terms of histological diagnosis, squamous cell carcinoma had significantly higher revision rates when compared to basal cell carcinoma (p < 0.05). Conclusions: To our knowledge, this is the first study to report the risk factors and predictors of revision surgery in patients undergoing MMS for nasal tumours. This study highlights that the reconstructive modality utilised affects the functional and cosmetic outcome of MMS. We note that ala complex subunit lesions, squamous cell carcinoma and flap reconstruction were associated with an increased risk of revision after Mohs reconstruction of nasal lesions. Level of evidence: Level III, risk/prognostic; therapeutic study. Trial registration number: (Ref: PLA-19-20_A03) 04/02/2020

Cellular Therapy for Wounds: Applications of Mesenchymal Stem Cells in Wound Healing

Despite progress in wound treatment including gene therapy, biological dresses and engineered skin equivalents, present treatment options for chronic wounds are restricted and not always effective. For example, inability to get consistent product from the introduced gene, biological covers may give rise to hypoxic conditions and engineered skin models are limited by their construction from substances which are hard to be degraded, and do not always result in complete replication into normal uninjured skin. A growing body of evidence suggests mesenchymal stem cells (MSCs), and their secreted growth factors and microvesicles, may potentiate the wound‐healing process and as such their addition to novel wound‐healing treatments may improve the efficacy of current therapeutic strategies. Recent studies report the ability of bone marrow‐derived MSCs (BM‐MSCs) to migrate and differentiate into skin cells in vivo

Differential effects of retinoic acid isomers on the expression of nuclear receptor co-regulators in neuroblastoma

AbstractRetinoic acid modulates growth and induces differentiation and apoptosis of neuroblastoma cells in vitro, with the all-trans and 9-cis isomers having different biological properties. Transcriptional activation in response to retinoic acid isomers is mediated by retinoic acid receptors and retinoid X receptors. The differential expression of co-activators and co-repressors which preferentially interact with retinoic acid receptors or retinoid X receptors may be a mechanism leading to different cellular responses to 9-cis and all-trans retinoic acid. To test this hypothesis, we have studied the expression of the nuclear receptor co-regulators TIF1α, TIF1β, SUG1 and SMRT in the N-type and S-type neuroblastoma cell lines SH SY 5Y and SH S EP. Transcripts for all four co-regulators were expressed in these neuroblastoma cells. The expression of TIF1α, TIF1β and SUG1 did not change in response to retinoic acid; however, SMRT was induced in both neuroblastoma cell lines, but particularly by all-trans retinoic acid in SH S EP cells. An additional co-activator, Trip3, was isolated by differential mRNA display and shown to be preferentially induced by 9-cis retinoic acid in SH SY 5Y and SH S EP cells. These data suggest that retinoic acid isomer-specific induction of nuclear receptor co-regulators may determine, in part, the differential biological effects of retinoic acid isomers

Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.

Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Exposure of Monocytic Cells to Lipopolysaccharide Induces Coordinated Endotoxin Tolerance, Mitochondrial Biogenesis, Mitophagy, and Antioxidant Defenses

In order to limit the adverse effects of excessive inflammation, anti-inflammatory responses are stimulated at an early stage of an infection, but during sepsis these can lead to deactivation of immune cells including monocytes. In addition, there is emerging evidence that the up-regulation of mitochondrial quality control mechanisms, including mitochondrial biogenesis and mitophagy, is important during the recovery from sepsis and inflammation. We aimed to describe the relationship between the compensatory immune and mitochondrial responses that are triggered following exposure to an inflammatory stimulus in human monocytic cells. Incubation with lipopolysaccharide resulted in a change in the immune phenotype of THP-1 cells consistent with the induction of endotoxin tolerance, similar to that seen in deactivated septic monocytes. After exposure to LPS there was also early evidence of oxidative stress, which resolved in association with the induction of antioxidant defenses and the stimulation of mitochondrial degradation through mitophagy. This was compensated by a parallel up-regulation of mitochondrial biogenesis that resulted in an overall increase in mitochondrial respiratory activity. These observations improve our understanding of the normal homeostatic responses that limit the adverse cellular effects of unregulated inflammation, and which may become ineffective when an infection causes sepsis

Established and Emerging Biomarkers in Cutaneous Malignant Melanoma

In an era of personalized medicine, disease specific biomarkers play an increasing role in the stratification of high-risk patient groups. Cutaneous malignant melanoma is the most deadly form of skin cancer with an ever-increasing global incidence, especially in patients under 35-years of age. Despite the excellent prognosis for patients diagnosed with early stage disease, metastatic disease still carries significant overall mortality. Biomarkers aim not only to identify high-risk patients, but also to provide potential therapeutic targets for differing patient subgroups. Furthermore, accessibility to tissue samples from a range of disease stages in malignant melanoma, unlike most other solid tissue tumours, provides the unique opportunity to explore the biology of tumour progression that may be relevant in the biology of cancer as a whole. Over the past decade, there have been major advances in targeted therapies, providing new avenues and hope to patients with this devastating disease. This review will focus on most up to date histological, serological and molecular biomarkers in malignant melanoma

Established and Emerging Biomarkers in Cutaneous Malignant Melanoma

In an era of personalized medicine, disease specific biomarkers play an increasing role in the stratification of high-risk patient groups. Cutaneous malignant melanoma is the most deadly form of skin cancer with an ever-increasing global incidence, especially in patients under 35-years of age. Despite the excellent prognosis for patients diagnosed with early stage disease, metastatic disease still carries significant overall mortality. Biomarkers aim not only to identify high-risk patients, but also to provide potential therapeutic targets for differing patient subgroups. Furthermore, accessibility to tissue samples from a range of disease stages in malignant melanoma, unlike most other solid tissue tumours, provides the unique opportunity to explore the biology of tumour progression that may be relevant in the biology of cancer as a whole. Over the past decade, there have been major advances in targeted therapies, providing new avenues and hope to patients with this devastating disease. This review will focus on most up to date histological, serological and molecular biomarkers in malignant melanoma

Induction of endoplasmic reticulum stress as a strategy for melanoma therapy: is there a future?

Melanoma cells employ several survival strategies, including induction of the unfolded protein response, which mediates resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Activation of oncogenes specifically suppresses ER stress-induced apoptosis, while upregulation of ER chaperone proteins and antiapoptotic BCL-2 family members increases the protein folding capacity of the cell and the threshold for the induction of ER stress-induced apoptosis, respectively. Modulation of unfolded protein response signaling, inhibition of the protein folding machinery and/or active induction of ER stress may thus represent potential strategies for the therapeutic management of melanoma. To this aim, the present article focuses on the current understanding of how melanoma cells avoid or overcome ER stress-induced apoptosis, as well as therapeutic strategies through which to harness ER stress for therapeutic benefit

Fateful music from a talented orchestra with a wicked conductor: Connection between oncogenic BRAF, ER stress, and autophagy in human melanoma

Autophagy and endoplasmic reticulum (ER) stress are involved in the development, progression, and chemoresistance of melanoma. We recently reported that oncogenic serine/threonine-protein kinase BRAF induces chronic ER stress, hence increasing baseline autophagy and promoting chemoresistance. The attenuation of ER stress restores basal autophagic activity and resensitizes melanoma cells to apoptosis